The present invention relates to acridone-derived compounds which are bisimidazoacridones, bistriazoloacridones and hybrid molecules having both imidazoacridone and triazoloacridone moieties. These compounds are useful as anti-neoplastic and anti-retroviral agents.
A number of acridine-based compounds which exhibit high antitumor activity recently have been reported. Cholody W. M., et al. (1990) described 5-[(Aminoalkly)amino]imidazo [4,5,1-de]acridin-6-ones as a novel class of antineoplastic agents (J. Med. Chem. 33:49-52 (1990). 8-Substituted 5- [(aminoalkyl)amino]-6H-v-triazolo [4,5,1-de]acridin-6-ones have also been described as potential antineoplastic agents (J. Med. Chem. 33:2852-2856 (1990)). The synthesis of chromophobe modified antineoplastic imidazaoacridones and their activity against murine leukemias has been described (J. Med. Chem. 35:378-382 (1992)). Capps, D. B., et al. described 2-(aminoalkyl)-5-nitropyrazolo [3,4, 5-k1] acridones as a new class of anticancer agents (J. Med. Chem. 35:4770-4778 (1992)).
The above compounds have a tetracyclic planar chromophore bearing one side chain containing an (aminoalkyl)amino residue as a common structural feature. It is believed that DNA is the primary target for these compounds and that they bind to DNA by intercalation.
Bifunctional compounds also have been studied as potential antitumor agents based upon the ability of acridones and other planar aromatic compounds to interact with DNA by intercalation. Chen, T. K., et al. (1978) studied diacridines as bifunctional intercalators (J. Med. Chem. 21:868-874 (1978)). Gaugain, B., et al. (1978) described the synthesis and conformational properties of an ethidium homodimer and an acridine ethidium heterodimer (Biochemistry 17:5071-5078 (1978)). Sinha, B. K., et al. (Biochemistry 17:5071-5078 (1977)) described the synthesis and antitumor properties of bis(quinaldine) derivatives (J. Med. Chem. 20:1528-1531 (1977)). Roques, B. P., et al. (1979) described the antileukemic activity of pyridocarbazole dimers (Biochem. Pharmacol 28:1811-1815 (1979)). Pelaprat, D. et al. (1980) described 7H-pyridocarbazole dimers as potential antitumor agents (J. Med. Chem. 23:1336-1343 (1980)). Brana, M. F., et al. (1993) described bis-naphtalimides as a class of antitumor agents (Anti-Cancer Drug Design 8:257-268 (1993)).
The rationale for the strong binding of bifunctional intercalators containing two aromatic ring systems joined by a suitable linker to nucleic acids has been presented (Canellakis, E. S., et al. Biochem Biophys. Acta 418:277-283 (1976). It was found that although such compounds exhibit high affinity for DNA, this strong binding with DNA by intercalation is generally not related to antitumor activity.
Many factors, such as physicochemical characteristics of the planar chromophores, nature of the linking chain (its length, rigidity and ionization state), position of attachment, and other factors, strongly influence the binding with DNA and the biological action of these compounds. Additionally, it was found that there is no direct correlation between DNA-binding affinity and cytotoxicity.
Since structure-activity relationships in the group of bifunctional intercalators in relation to their in vivo antitumor action remain unclear, it is not possible to predict structures that will show such activity. Small structural modifications can drastically change biological properties of the agent. Accordingly, a goal exists to find other compounds with high antineoplastic activity, especially selectively directed towards specific tumors.
It was previously disclosed that certain bisimidazoacridones, the closely related bistriazoloacridones and hybrid molecules containing both the imidazoacridone and triazoloacridone moieties were potent but selective antitumor agents (U.S. Pat. No. 5,508,289).
This invention relates to a novel class of acridine-based compounds and their use as antineoplastic agents and as antiretroviral agents. It has further been found that the bismidazocridones, the bistriazoloacridones and hybrid molecules disclosed in U.S. Pat. No. 5,508,289 are useful as antiretroviral agents.
The present invention relates to compounds having the following general formula (I): 
wherein R1 and R2 are independently xe2x80x94H, xe2x80x94OH, amino, alkylamino, dialkylamino, alkoxy, alkyl, haloalkyl or halogen; n is 2 to 6, X and Xxe2x80x2 are independently xe2x80x94N or xe2x80x94NO2; Y and Yxe2x80x2 are independently xe2x80x94N or xe2x80x94CH, or xe2x80x94H; and the double-slash represents a double bond or no bond; such that when X or Xxe2x80x2 is xe2x80x94N, Y or Yxe2x80x2 is xe2x80x94CH or xe2x80x94N, and the double-slash is a double bond, and when X or Xxe2x80x2 is xe2x80x94NO2, Y or Yxe2x80x2 is xe2x80x94H, and the double slash is no bond.
The present invention also provides a pharmaceutical composition comprising at least one of the above compounds and a pharmaceutically acceptable carrier.
The present invention further provides a method for treating a neoplastic cell growth in a subject in need of such treatment which comprises administering to the subject an amount of the pharmaceutical composition above effective to treat the neoplastic cell growth.
The present invention still further provides a method for treating retroviral infections in a population of cells including human cells comprising contacting the cell population or administering to a subject having retroviral infected cells an effective amount of at least one compound of the formula (I).
Also included within the scope of the present invention is a method for protecting a population of cells including human cells against retroviral pathogenesis comprising contacting or treating said cells with an anti-retroviral effective amount of at least one compound according to formula (I).
A yet still further aspect of the present invention provides a method of treating retroviral infections in a population of cells including human cells comprising administering and/or contacting the cells of a subject having retroviral infected cells an effective amount of at least one compound of formula (II): 
wherein R is H, alkyl, or a grouping which makes the compound function as a prodrug; n is 2 to 6; and R1, R2, X, Y, Xxe2x80x2 or Yxe2x80x2 and the double dash is as defined hereinabove for formula (I).